KR102426727B1 - oral drug delivery system controlling release rate AND manufacturing method for oral drug delivery system controlling release rate - Google Patents

Abstract

The present invention relates to an oral drug delivery device with controlled release rate and a method for manufacturing an oral drug delivery device with controlled release rate. Disclosed are a release rate controlled oral drug delivery device that allows a drug to be continuously released at a specific rate through a release opening of the device, and a method for manufacturing the same.

Description

BACKGROUND ART A drug delivery device for controlling release rate and a method for manufacturing an oral drug delivery device with controlled release rate

The present invention relates to an oral drug delivery device with controlled release rate and a method for manufacturing an oral drug delivery device with controlled release rate. Disclosed are a release rate controlled oral drug delivery device that allows a drug to be continuously released at a specific rate through a release opening of the device, and a method for manufacturing the same.

An oral sustained release drug delivery system is a drug delivery system designed to continuously release a drug over a long period of time when administered orally. The sustained release of the drug can extend the duration of the drug's action, thereby reducing the number of administrations, and thus improving the patient's medication compliance. In addition, if the drug release rate is constant, the blood drug concentration is stabilized, thereby avoiding the low therapeutic effect or toxicity caused by the fluctuation of the drug concentration, thereby ultimately improving the drug treatment efficiency.

Conventionally, the technology used for oral sustained-release formulation can be largely divided into a diffusion-controlled system, a solvent-activated system, and a chemically controlled system. Specifically, the diffusion control system includes a matrix system and a membrane control system using a polymer, coated granules and microspheres, tablets, and the like. Solvent activation systems include osmotic pressure control or drug release control technology by polymer swelling. Finally, the chemical control system involves the release of drugs from the resin by chemical degradation or erosion of polymers or chemical action.

For example, Korean Patent Publication Nos. 2012-0116545, 2017-0141524, and 2018-0024408 disclose a sustained-release tablet matrix system that controls the release rate of a drug using a hydrophilic polymer or a sustained-release layer and an immediate-release layer. A multi-layered tablet matrix system is reported. In addition, Korean Patent Application Laid-Open No. 2018-0092981 discloses a controlled-release pharmaceutical composition using an osmotic pump, and 2008-0108520 discloses a sustained-release formulation containing a drug and an ion exchange resin complex.

However, most of these conventional sustained-release drug delivery systems delay the release rate of the drug due to the interaction between the drug and the release-controlling mechanism. do. In addition, many trials and errors are repeated in order to develop a formulation having a specific release rate. As a result, the existing methods have the disadvantage that it takes a lot of time and money to develop a sustained-release drug delivery system.

Therefore, it is necessary to develop a release rate control oral drug delivery device that can overcome the limitations of the conventional sustained-release drug delivery system technology for oral use.

Republic of Korea Patent Publication No. 2012-0116545

The present invention has been devised to solve the above problems, and when a formulation containing a main drug is inserted into the drug delivery device and administered, the drug is eluted by the gastric juice flowing into the device, and the eluted drug is discharged through a predetermined outlet. An object of the present invention is to provide an oral drug delivery device with a controlled release rate that can be continuously released to the outside at a predetermined rate through the

An oral drug delivery device for controlling a release rate according to an embodiment of the present invention comprises: a capsule body having a drug storage space with an open upper portion; a capsule cap coupled to the capsule body and covering the medicament storage space from above; an insert positioned in the medicament storage space and disposed under the capsule cap and vertically displaceable in the medicament storage space; and a first agent consisting of a three-dimensional object having a predetermined height, positioned in the medicament storage space, and disposed between the capsule cap and the insert to space the capsule cap and the insert; and a second agent disposed in the medicament storage space and disposed under the insert.

The capsule body includes a lateral opening laterally opened to open the medicament storage space laterally, and a discharge opening positioned below the lateral opening to open the medicament storage space, wherein the insert is vertically including a through hole, and when the first agent is positioned between the insert and the capsule cap, the lateral opening is in an open state, and the medicament storage space is opened to the outside through the lateral opening and the through hole, When the first agent is removed and the distance between the insert and the capsule cap is reduced, the insert covers the lateral opening so that the lateral opening is closed and the second agent is released through the release opening.

According to one embodiment, the emitting opening has a smaller penetration area than the lateral opening.

According to one embodiment, the capsule cap includes a first magnetic member, the insert includes a second magnetic member, the first magnetic member and the second magnetic member generate an attractive force between each other, When the first agent is removed, the insert is displaced in the capsule cap direction by the attractive force between the first magnetic member and the second magnetic member.

According to an embodiment, the insert includes a side wall portion constituting a side circumferential surface of the insert, and the side wall portion closes the side opening from the inside when the insert is in a closed state.

According to an embodiment, the insert includes a support surface portion for supporting the first agent under the first agent.

In one embodiment, the second magnetic member is fixed to the support surface portion.

According to one embodiment, the first magnetic member is fixed to the lower surface of the capsule cap.

According to one embodiment, the dissolution rate of the first agent has a configuration that is faster than the dissolution rate of the second agent.

According to an embodiment, the first formulation includes a component in which lactose (Flow-lac 100) and magnesium stearate are mixed in a ratio of 99.5:0.5.

According to one embodiment, the capsule cap has a gas filling space in which the gas is contained and has buoyancy.

In one embodiment, there is provided a method for manufacturing an oral drug delivery device with controlled release rate, the method comprising: manufacturing the capsule body, the capsule cap, and the insert; preparing the first formulation; and after injecting the second agent into the capsule body, disposing the insert and the first agent and coupling the capsule cap; includes

The release rate control device for oral drug delivery according to an embodiment of the present invention can control the release rate of the main drug from the drug formulation.

In particular, since the release of the main drug occurs at a specific rate depending on structural factors such as the location and size of the release opening, the drug release rate can be appropriately selected.

Therefore, the oral drug delivery device with controlled release rate of the present invention does not need to create a new formulation by adding other release rate controlling additives to the formulation like conventional sustained-release formulations, and simply inserts the drug formulation into the oral drug delivery device with controlled release rate. By inserting, the release rate of the drug can be controlled.

In addition, since the release rate of the main drug is determined by the structure of the release rate control oral drug delivery device, it is possible to accurately control the release rate regardless of the type of the main drug.

In addition, the first formulation including the fast-disintegrating tablet may be prepared to contain the main drug, and through this, an initial loading dose may be additionally administered to reach an effective blood concentration within a short time after administration.

In addition, according to the embodiment, the capsule cap has a gas filling space that provides buoyancy. Therefore, the oral drug delivery device for controlling the release rate according to an embodiment of the present invention may be in a state of floating on the gastrointestinal fluid. Therefore, the release rate controlled oral drug delivery device of the present invention can stay in the stomach of the user for a sufficient time until the release of the main drug is completed.

Overall, the release rate-controlled oral drug delivery device according to the embodiment does not use a release-controlling additive necessary for controlling the release of a conventional sustained-release formulation, and can easily control the release rate of the drug formulation without a complex formulation development process. have.

The oral drug delivery device for controlling the release rate according to an embodiment of the present invention can be widely applied to commercial drug formulations of various drugs. In particular, the absorption site, which has been difficult to develop a sustained release formulation by the conventional method, is the upper part of the gastrointestinal tract. It can be applied to drugs that are scissors, drugs that are unstable in the lower intestine, etc. to improve bioavailability and increase the therapeutic effect.

1 is a view showing the external appearance of the release rate controlled oral drug delivery device according to an embodiment of the present invention, Figure 2 is an exploded view of the release rate controlled oral drug delivery device according to the embodiment of the present invention. FIG. 3 is a cross-sectional view taken along line XX of FIG. 1 .
Figure 4 is a view showing the capsule body of the release rate control oral drug delivery device according to an embodiment of the present invention, Figure 5 is a view showing a cross-section of X1-X1 of FIG.
6 is a view showing a capsule cap of the oral drug delivery device for controlling the release rate according to an embodiment of the present invention, and FIG. 7 is an exploded view showing a cross section of X2-X2 of FIG. 6 .
8 is a view showing the insert of the release rate control oral drug delivery device according to an embodiment of the present invention, FIG. 9 is a view showing a cross-section of X3-X3 of FIG.
Figure 10 is a view showing the external appearance of the release rate control oral drug delivery device according to an embodiment of the present invention, Figure 11 is a cross-sectional view showing X4-X4 of Figure 10.
12 shows a state in which the first agent is removed, and FIG. 13 shows a cross section of X5-X5 of FIG. 12 .
14 and 15 are diagrams showing the dissolution test results of the release rate control oral drug delivery device according to an embodiment of the present invention.
16 is a view showing the dissolution test results of the release rate control oral drug delivery device according to an embodiment of the present invention.

Hereinafter, with reference to the accompanying drawings, a preferred embodiment according to the present invention will be described.

1 is a view showing the external appearance of a controlled release rate oral drug delivery device according to an embodiment of the present invention, Figure 2 is an exploded view of the release rate controlled oral drug delivery device according to an embodiment of the present invention. FIG. 3 is a cross-sectional view taken along line X-X of FIG. 1 .

In the following description, terms indicating a direction such as "up and down" refer to the matters shown in the drawings. However, this direction is not absolute, and may vary depending on the viewing direction and the orientation of the member.

An oral drug delivery device for controlling a release rate according to an embodiment of the present invention, the capsule body 100; capsule cap 200; an insert 300 , comprising: a first agent 400 ; and a second agent 500 may be further included.

<Capsule body (100)>

4 is a view showing the capsule body 100 of the release rate control oral drug delivery device according to an embodiment of the present invention, FIG. 5 is a view showing a cross-section of X1-X1 of FIG.

The capsule body 100 is a member having a medicament storage space 120 in the main body 110 . The drug storage space 120 has an open top.

A second agent 500 to be described later may be contained in the drug storage space 120 . In addition, the insert 300 may be disposed in the medicament storage space (120). In addition, the first agent 400 may be disposed on the insert 300 .

According to an embodiment, the capsule body 100 comprises a lateral opening 130 and a discharge opening 140 .

The lateral opening 130 is a predetermined through hole 320 passing through the main body 110 in the lateral direction. The medicament storage space 120 is laterally opened by the lateral opening 130 . A plurality of side openings 130 may be provided. The plurality of side openings 130 may be positioned side by side along the circumference of the capsule body 100 .

The discharge opening 140 is a predetermined through hole 320 passing through the main body 110 . The discharge opening 140 is located below the lateral opening 130 . The medicament storage space 120 is opened to the outside by the discharge opening (140). A plurality of emission openings 140 may be provided. In the drawings, the discharge opening 140 is provided on the side of the capsule body 100 and is opened in the lateral direction, but it is not limited thereto, and the discharge opening 140 may be formed in the lower portion of the capsule body 100 .

According to an embodiment, the discharge opening 140 may have a smaller penetration area than the lateral opening 130 . Accordingly, the hourly flow of fluid (eg, bodily fluid, etc.) through the lateral opening 130 is greater than the hourly flow of fluid through the discharge opening 140 .

<Capsule Cap (200)>

6 is a view showing the capsule cap 200 of the release rate control oral drug delivery device according to an embodiment of the present invention, FIG. 7 is a view showing a cross-section of X2-X2 of FIG. 6 in an exploded view.

The capsule cap 200 is a member coupled to the capsule body 100 . When the capsule cap 200 is coupled to the capsule body 100 , the capsule cap 200 covers the medicament storage space 120 from above. That is, the capsule cap 200 is a cap member covering the medicament storage space 120 .

The capsule cap 200 has a cap body 210 , and a fitting protrusion 220 that can be inserted and inserted into the upper end of the capsule body 100 may be provided on the lower surface of the cap body 210 .

The capsule cap 200 includes a first magnetic member 230 . The first magnetic member 230 may be a member having a magnetic force or a member drawn in a magnetic force direction in response to a magnetic force generated from an external magnetic force source.

According to the embodiment, the first magnetic member 230 may be fixed to the lower surface of the capsule cap 200 . For example, a predetermined fixing groove 240 is provided on the lower surface of the capsule cap 200 , and the first magnetic member 230 may be fitted into the fixing groove 240 . In addition, a predetermined fixing member 250 capable of fixing the first magnetic member 230 to the capsule cap 200 may be provided. For example, the fixing member 250 may cover the first magnetic member 230 from below.

In addition, according to the embodiment, the capsule cap 200 may have a gas filling space 260 therein. The gas filling space 260 is sealed, and gas may be contained therein.

As the capsule cap 200 has a gas filling space 260 as in the above embodiment, the oral drug delivery device for controlling the release rate may be taken by the user and float on the gastric juice in the stomach.

<Insert (300)>

Figure 8 is a view showing the insert 300 of the release rate control oral drug delivery device according to an embodiment of the present invention, Figure 9 is a view showing a cross section of X3-X3 of Figure 8. Here, in FIG. 9 , the first agent 400 is placed on the insert 300 .

The insert 300 is located in the medicament storage space 120 , is disposed under the capsule cap 200 , and is a member that is vertically displaceable in the medicament storage space 120 .

According to an embodiment, the insert 300 may include a side wall portion 310 constituting a side circumferential surface of the insert 300 . The side wall portion 310 may have a shape corresponding to the inner circumferential surface of the capsule body 100 . For example, the side wall portion 310 may have a cylindrical shape having a predetermined radius and height. The outer circumferential surface of the side wall portion 310 may be in close contact with the inner circumferential surface of the capsule body 100 when the insert 300 is put into the medicament storage space 120 or may face with a fine interval. Therefore, when the insert 300 is viewed from above, the outer shape of the insert 300 corresponds to the outer shape of the medicament storage space 120 , and the cross-sectional area may also correspond. Here, the meaning of corresponding means about the same degree.

According to the embodiment, the insert 300 may have a through hole 320 opened up and down. The through hole 320 is formed inside the side wall portion 310 .

According to an embodiment, the insert 300 may include a support surface part 330 crossing the side wall part 310 . Accordingly, the through hole 320 may pass through both sides of the support surface portion 330 , respectively.

According to the embodiment, the insert 300 includes the second magnetic member 340 . The second magnetic member 340 may be a member having a magnetic force or a member drawn in a magnetic force direction in response to a magnetic force generated from an external magnetic force source.

According to an embodiment, the second magnetic member 340 may be fixed to the support surface part 330 . According to an embodiment, a predetermined fixing groove 350 to which the second magnetic member 340 is fixed may be provided at a lower portion of the support surface part 330 .

<The first agent 400 and the second agent 500>

The first formulation 400 is located in the medicament storage space 120 and is disposed between the capsule cap 200 and the insert 300 .

The first formulation 400 is composed of a three-dimensional material having a predetermined height and spaced between the insert 300 and the capsule cap 200 .

The second formulation 500 is located in the medicament storage space 120 and is located below the insert 300 .

According to an embodiment, the reaction rate of the first agent 400 with respect to one body fluid may be faster than the reaction rate of the second agent 500 with respect to the one body fluid.

That is, the first formulation 400 is a fast-disintegrating tablet having a relatively fast reaction rate, and the second formulation 500 may be a predetermined general-release formulation having a slower reaction rate than the fast-disintegrating tablet. However, the present invention is not limited thereto, and the component of the second formulation 500 may include other drug formulations.

According to an embodiment, the first formulation 400 may have a component in which lactose (Flow-lac 100) and magnesium stearate are mixed in a ratio of 99.5:0.5.

<Combination structure, operation and effect of oral drug delivery device with controlled release rate>

Hereinafter, the coupling structure, operation and effect of each part of the release rate controlled oral drug delivery device according to the embodiment will be described.

10 is a view showing the external appearance of an oral drug delivery device for controlling the release rate according to an embodiment of the present invention, and FIG. 11 is a cross-sectional view showing X4-X4 of FIG. 10 . ( FIGS. 10 and 11 are the same as FIGS. 1 and 3 , respectively)

First, a state in which the first formulation 400 is disposed between the capsule cap 200 and the insert 300 will be described. That is, a state in which the insert 300 and the capsule cap 200 are expanded and spaced apart from each other will be described.

The second agent 500 is contained in the medicament storage space 120 of the capsule body 100 , and then the insert 300 is disposed. The first agent 400 is disposed on the insert 300 . On the other hand, the insert 300 may be displaced up and down in the medicament storage space (120).

In a state in which the insert 300 , the first agent 400 , and the second agent 500 are disposed in the drug storage space 120 as described above, the capsule cap 200 is coupled to the capsule body 100 . For example, the coupling protrusion 220 of the capsule cap 200 may be interpolated into the upper end of the capsule body 100 .

In the coupled state as described above, the first agent 400 is positioned between the insert 300 and the capsule cap 200 . In addition, the first magnetic member 230 of the capsule cap 200 is positioned on the first agent 400 , and the second magnetic member 340 of the insert 300 is positioned below the second agent 500 .

In this case, the first magnetic member 230 and the second magnetic member 340 generate an attractive force between them. For example, when both the first magnetic member 230 and the second magnetic member 340 have magnetic force, the first magnetic member 230 and the second magnetic member 340 may face each other with different magnetic poles. As another example, one of the first magnetic member 230 and the second magnetic member 340 may have a magnetic force and the other may be made of a material that responds to the magnetic force.

As described above, the first magnetic member 230 and the second magnetic member 340 generate attractive force to each other. However, since the first agent 400 is positioned between the insert 300 and the capsule cap 200 , the insert 300 and the capsule cap 200 are spaced apart by the first agent 400 . That is, the first agent 400 may function to space the insert 300 and the capsule cap 200 apart by resisting the attractive force between the second magnetic member 340 of the first magnetic member 230 .

In a state where the first agent 400 is disposed between the insert 300 and the capsule cap 200 , the insert 300 is positioned below the lateral opening 130 . Accordingly, the side opening 130 is in an open state. In such an open state of the side opening 130 , the space inside the side opening 130 is opened to the outside through the side opening 130 .

In addition, the insert 300 has a through hole 320 opened up and down. Accordingly, the space positioned under the insert 300 is also opened to the outside through the through hole 320 and the side opening 130 .

By having the above configuration, when the oral drug delivery device for controlling the release rate according to the embodiment of the present invention is put into the liquid, the liquid is introduced into the drug storage space 120 through the lateral opening 130 and the through hole 320. can be imported.

Hereinafter, a state in which the first agent 400 is removed will be described. 12 shows a state in which the first agent 400 is removed, and FIG. 13 shows a cross-section of X5-X5 of FIG. 12 .

For example, when the first agent 400 is dissolved in the liquid introduced through the lateral opening 130 , it may be removed between the insert 300 and the capsule cap 200 . When the first agent 400 is removed between the insert 300 and the capsule cap 200, the attractive force between the first magnetic member 230 of the capsule cap 200 and the second magnetic member 340 of the insert 300 Thus, the insert 300 is displaced in the capsule cap 200 direction (upward).

When the insert 300 is displaced in the capsule cap 200 direction and the distance between the insert 300 and the capsule cap 200 is reduced, at least a portion of the lateral opening 130 is covered by the insert 300 . become a state That is, the side opening 130 is closed by the side wall portion 310 of the insert 300 is in a closed state. In such a closing state of the side opening 130, the flow (inflow, outflow) of the fluid between the inside and the outside of the medicament storage space 120 through the side opening 130 may be blocked or minimized. Meanwhile, in the drawings, the upper end of the insert 300 is shown in contact with the lower surface of the capsule cap 200 , but the present invention is not limited thereto.

On the other hand, in spite of the closing state of the side opening 130 as described above, the discharge opening 140 maintains an open state. Accordingly, the fluid inside the medicament storage space 120 may be eluted to the outside through the discharge opening 140 . As described above, since the size of the discharge opening 140 is smaller than that of the lateral opening 130 , the hourly flow rate of the fluid through the discharge opening 140 can be limited relatively small.

Hereinafter, when the release rate control oral drug delivery device according to an embodiment of the present invention is taken by a user and injected into the stomach will be described.

In the release rate control oral drug delivery device according to an embodiment of the present invention, the first formulation 400 is positioned between the capsule cap 200 and the insert 300 so that the lateral opening 130 is open to the user's It is injected into the stomach (oral administration). When the release rate control oral drug delivery device is inserted into the stomach, the gastrointestinal fluid in the stomach flows into the space located inside the lateral opening 130 through the lateral opening 130 . In addition, the gastrointestinal fluid is also introduced into the space located below the insert 300 through the through hole (320).

Accordingly, the first agent 400 positioned on the insert 300 may be dissolved by the gastrointestinal fluid introduced through the lateral opening 130 . Accordingly, the insert 300 is displaced in the capsule cap 200 direction by the attractive force between the first magnetic member 230 and the second magnetic member 340 , and the lateral opening 130 is in a closed state. When the side opening 130 is in the closed state, the gastrointestinal fluid may not flow into the drug storage space 120 or only a small amount may be introduced.

At this time, since the first formulation 400 is a fast-disintegrating tablet, it can rapidly react to the gastrointestinal fluid and dissolve quickly. When the release rate control oral drug delivery device according to an embodiment of the present invention is taken by a user and put into the stomach, the first agent 400 is quickly dissolved and the lateral opening 130 may be in a closed state.

In addition, the first formulation 400 may not contain a drug component, or may contain an initial dose of the main drug component. If the first formulation 400 contains the initial dose of the main drug component, an effective blood concentration can be achieved within a short period of time at the initial stage of administration.

In addition, the second agent 500 contained in the space located under the insert 300 may be dissolved in response to the gastrointestinal fluid introduced through the lateral opening 130 and the through hole 320 .

Although the side opening 130 is in the closed state, the discharge opening 140 maintains an open state. Accordingly, the dissolved second agent 500 may be eluted to the outside through the release opening 140 . As described above, since the size of the discharge opening 140 is smaller than that of the lateral opening 130 , the hourly flow rate of the fluid through the discharge opening 140 is relatively small.

Accordingly, the dissolved second agent 500 may be gradually released into the body through the release opening 140 while the release rate controlled oral drug delivery device of the present invention stays in the stomach of the user. In this case, the shape, size, and position of the discharge opening 140 may be appropriately selected. Accordingly, the release rate of the second agent 500 may also be appropriately adjusted. At this time, since the second formulation 500 includes the main drug component, the release rate of the main drug component can be appropriately adjusted.

As described above, in the oral drug delivery device for controlling the release rate according to an embodiment of the present invention, the drug formulation containing the main drug is included in the second formulation 500 for oral administration. The release rate control device for oral drug delivery according to an embodiment of the present invention can control the release rate of the main drug from the drug formulation.

In particular, since the release of the main drug occurs at a specific rate depending on structural factors such as the location and size of the release opening 140, the drug release rate can be appropriately selected.

Therefore, the oral drug delivery device with controlled release rate of the present invention does not need to create a new formulation by adding other release rate controlling additives to the formulation like conventional sustained-release formulations, and simply inserts the drug formulation into the oral drug delivery device with controlled release rate. By inserting, the release rate of the drug can be controlled.

In addition, since the release rate of the main drug is determined by the structure of the release rate control oral drug delivery device, it is possible to accurately control the release rate regardless of the type of the main drug.

In addition, the first formulation 400 including the fast-disintegrating tablet may be prepared to contain the main drug, and through this, an initial loading dose may be additionally administered to reach an effective blood concentration within a short time after administration.

In addition, according to the embodiment, the capsule cap 200 has a gas filling space 260 that provides buoyancy. Therefore, the oral drug delivery device for controlling the release rate according to an embodiment of the present invention may be in a state of floating on the gastrointestinal fluid. Therefore, the release rate controlled oral drug delivery device of the present invention can stay in the stomach of the user for a sufficient time until the release of the main drug is completed.

Overall, the release rate-controlled oral drug delivery device according to the embodiment does not use a release-controlling additive necessary for controlling the release of a conventional sustained-release formulation, and can easily control the release rate of the drug formulation without a complex formulation development process. have.

The oral drug delivery device for controlling the release rate according to an embodiment of the present invention can be widely applied to commercial drug formulations of various drugs. In particular, the absorption site, which has been difficult to develop a sustained release formulation by the conventional method, is the upper part of the gastrointestinal tract. It can be applied to drugs that are scissors, drugs that are unstable in the lower intestine, etc. to improve bioavailability and increase the therapeutic effect.

<Method for manufacturing an oral drug delivery device with controlled release rate>

A method of manufacturing an oral drug delivery device for controlling a release rate according to an embodiment of the present invention includes manufacturing a capsule body 100 , a capsule cap 200 and an insert 300 ; preparing a first formulation 400; and placing the second agent 500 , the insert 300 , and the first agent 400 in the capsule body 100 and coupling the capsule cap 200 .

The capsule body 100, the capsule cap 200, and the insert 300 are a material selected from the group consisting of separate biodegradable synthetic polymers that do not contain main drug components, natural polymers, synthetic resins for oral administration, and mixtures thereof. can be configured. In addition, as long as conventionally used synthetic resins and natural polymers for oral administration are not particularly limited, they may be used. These materials do not dissolve in the stomach and can remain in the stomach for a sufficient time until the drug release is completed, and after the drug release is complete, it can be excreted out of the body through the small intestine.

The capsule body 100, the capsule cap 200, and the insert 300 may be designed and manufactured using, for example, a 3D printer, and may be manufactured and mass-produced by a conventionally known mold method.

In the step of manufacturing the capsule body 100, the release opening 140 provided in the capsule body 100 may be appropriately selected in shape, position, and number. Therefore, it is possible to control the dissolution profile of the drug released through the release opening (140). In addition, by deriving a mathematical relationship between the size, number, and location of the release opening 140 and the release rate of the drug, it is possible to manufacture an oral drug delivery device for controlling the release rate having a desired release rate.

As an example of a drug formulation that may be included in the second formulation 500 included in the release rate control oral drug delivery device of the present invention, baclofen, riboflavin, acyclovir, rebamipide, furosemide, levodopa, albuterol , 5-fluorouracil, an antacid, captopril, diazepam, diltiazem, propranolol, and the like. However, drug preparations such as drugs with good absorption rate mainly in the stomach, drugs absorbed in the upper small intestine, drugs acting on the stomach, and drugs unstable in the lower small intestine are all possible. This drug formulation can be prepared as a fast-disintegrating tablet containing the main component of the drug, or a commercially available formulation can be used as it is.

<An oral drug delivery device with controlled release rate according to the embodiment, and a method for manufacturing an oral drug delivery device with controlled release rate>

Hereinafter, in detail, the manufacture of the release rate controlled oral drug delivery device according to an embodiment of the present invention will be described in detail. However, the following description is merely an example, and does not limit the scope of the present invention.

<Examples 1 to 9>

<Step 1: Manufacturing the capsule body 100, the capsule cap 200 and the insert 300>

Rhino 6® (Robert McNeel & Associates, WA, USA) computer-aided design (CAD) program was used to complete the design of the release rate control oral drug delivery device according to the embodiment of the present invention. Then, using a 3D printer (Raise3D N2 model) of a fused deposition modeling (FDM) method and poly lactic acid resin to configure the drug delivery device under 3D printing printing conditions as shown in Table 1 below 1) having a gas filling space 260 A capsule cap 200, 2) a capsule body 100 including a medicament storage space 120, a lateral opening 130, and a release opening 140, and 3) an insert 300 were produced.

In addition, various types of capsule bodies 100 were manufactured by varying the size, number, and positions of the release openings 140 provided in the capsule body 100, and are shown in Table 2 (Preparation Examples 1-1 to 1-9) . Here, the position of the discharge opening 140 means a height from the lower end of the capsule body 100 . For example, in Preparation Example 1-1, the discharge opening 140 is located 3.3 mm above the lower end of the capsule body 100 . In all the descriptions below, the position of the discharge opening 140 may be understood to mean a height from the lower end of the capsule body 100 .

print parameters Filament diameter PLA 1.75mm Nozzle diameter 0.2 mm Build plate temperature 80℃ Infill Density 100% Shells 2 Layer height 0.15 mm

Preparation 1-1 Preparation 1-2 Preparation 1-3 Preparation Example 1-4 Preparation 1-5 Preparation 1-6 Preparation 1-7 Preparation 1-8 Preparation 1-9 Size of drug outlet (mm ² ) 0.09 0.36 0.09 0.36 0.09 0.36 0.09 0.36 0.225 Number of drug outlets 2 2 6 6 2 2 6 6 4 Position of drug outlet (mm) 3.3 3.3 3.3 3.3 9.3 9.3 9.3 9.3 6.3

<Step 2: Preparing the first formulation 400>

As a component constituting the first formulation 400, lactose (Flow-lac 100) and magnesium stearate were homogeneously mixed in a ratio of 99.5:0.5. The prepared mixture was compressed into a fast disintegrating tablet having a diameter of 5 mm and a height of 3.5 mm using a hydraulic tablet press (Carver, Inc.) and a circular punch (diameter: 5 mm) at a pressure of 0.3 ton. The manufacturing method of the prepared fast-disintegrating tablet is shown in Table 3 below (Preparation Example 2).

Manufacturing method Preparation 2 Usage (mg/T) weight (%) excipient Flow-lac 100 87.0625 99.5 lubricant magnesium stearate 0.4375 0.5 Total mass (mg) 87.5 Compression pressure (ton) 0.3

<Step 3: Placing the second agent 500, the insert 300, and the first agent 400 in the capsule body 100 and coupling the capsule cap 200>

Among the parts manufactured in Preparation Examples 1-1 to 1-9 of Step 1, the first magnetic member 230 and the second magnetic member 340 are mounted on the lower end of the capsule cap 200 and the upper end of the insert 300, respectively. then assemble In addition, the first formulation 400 prepared in Preparation Example 2 of step 2 and the commercially available 10 mg baclofen drug formulation (Prex tab®) were inserted into the capsule body 100 as the second formulation 500 . Accordingly, an oral drug delivery device for controlling the drug release rate according to an embodiment of the present invention was prepared. (Examples 1 to 9) Each configuration of each manufactured part is shown in Table 4 below.

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Capsule body (100), capsule cap (200), insert (300) Preparation 1-1 Preparation 1-2 Preparation 1-3 Preparation Example 1-4 Preparation 1-5 Preparation 1-6 Preparation 1-7 Preparation 1-8 Preparation 1-9 first agent (400) Preparation 2 second agent (500) Baclofen 10 mg (Prex tab ^® )

Hereinafter, performance experimental examples of the release rate controlled oral drug delivery device prepared in Examples 1 to 9 will be described.

<Experimental Example 1: Floating force experiment of release rate-controlled oral drug delivery device prepared according to Examples 1 to 9>

An experiment was conducted to confirm the floating power of the release rate-controlled oral drug delivery device prepared in Examples 1 to 9. For the above evaluation, a dissolution test was performed in a pH 1.2 solution according to the second method of the dissolution test method of the Korean Pharmacopoeia, and the conditions of the dissolution test are shown in Table 5 below. As a result of measuring the floating time in the eluate, the floating time was maintained for 24 hours or more in Examples 1 to 9. It was confirmed that the buoyancy caused by the portion of the capsule cap 200 including the gas filling space 260 was not abnormal in that the release rate control oral drug delivery device floated for a sufficient time until the drug release was completed.

dissolution test method Korean Pharmacopoeia General Test Method 2 (Paddle Method) temperature 37 ± 0.5°C Paddle rotation speed 100 rpm eluate liquid pH 1.2 eluate volume 900 mL

<Experimental Example 2: Dissolution test of controlled release rate oral drug delivery device>

In order to confirm the dissolution of the second formulation 500 consisting of 10 mg of commercially available baclofen and Examples 1 to 9, a dissolution test was performed in a pH 1.2 solution according to the second method of the dissolution test method of the Korean Pharmacopoeia. The conditions of the dissolution test are as shown in Table 5 above, and the baclofen drug concentration in the eluate was analyzed by HPLC-UV. The analysis conditions for baclofen are shown in Table 6.

machine HPLC Waters 2695 separations module (Waters, Milford, CA, USA) UV detector Waters 2996 photodiode array detector (Waters, Milford, CA, USA) HPLC conditions analysis column Zorbax 300SB-C18, 5.0 μm, 4.6 X 250 mm (Agilent Technologies, Torrance, CA, USA) Absorbance λ 220 nm mobile phase 10 mM sodium phosphate buffer: acetonitrile = 70: 30 flow rate 1 mL/min Column oven temperature 30°C injection volume 20 μL

The results obtained through the dissolution test are shown in FIGS. 14 and 15 . As shown in FIGS. 14 and 15 , when the dissolution test was performed by inserting the 10 mg general release tablet of baclofen into the release rate control oral drug delivery device of the present invention, the release opening 140 of the capsule body 100 part. It was confirmed that the time required for 80% dissolution could be controlled from 1 hour to 6 hours or more depending on the size, number, and location conditions.

<Examples 10 to 12: Optimization of Release Rate Controlled Oral Drug Delivery Device>

Based on the results of Experimental Example 1 and Experimental Example 2 of Examples 1 to 9, the time taken for 80% dissolution in the dissolution test by changing the size, number, and location of the release opening 140 of the capsule body 100 part (T80) ) were prepared for oral drug delivery devices with controlled release rates expected to be 2, 4, and 6 hours, respectively.

<Step 1: Manufacturing the capsule body 100, the capsule cap 200 and the insert 300>

Rhino 6® (Robert McNeel & Associates, WA, USA) computer-aided design (CAD) program was used to complete the design of the release rate controlled oral drug delivery device according to the embodiment of the present invention. Then, using a fused deposition modeling (FDM) type 3D printer (Raise3D N2 model) and poly lactic acid resin to configure the drug delivery device under 3D printing printing conditions as shown in Table 1 below 1) having a gas filling space 260 A capsule cap 200, 2) a capsule body 100 including a medicament storage space 120, a lateral opening 130, and a release opening 140, and 3) an insert 300 were produced.

In addition, by predicting the size, number, and location of the release opening 140 such that the time to reach 80% dissolution (T80) is 2 hours, 4 hours, and 6 hours, release rate control oral drug delivery having a desired release rate The device was prepared and summarized in Table 7 (Preparation Examples 1-10 to 1-12).

Preparation Example 1-10 Preparation 1-11 Preparation 1-12 Target value of time to 80% dissolution (T80) (h) 2 4 6 The size of the discharge opening 140 (mm ² ) 0.36 0.36 0.09 Number of discharge openings 140 6 6 2 Location of discharge opening 140 (mm) 4.95 7.5 8.1

<Step 2: Preparing the first formulation 400>

As a component constituting the first formulation 400, lactose (Flow-lac 100) and magnesium stearate were homogeneously mixed in a ratio of 99.5:0.5. The prepared mixture was prepared by tableting a fast-disintegrating tablet having a diameter of 5 mm and a height of 3.5 mm using a hydraulic tablet press (Carver, Inc.) and a circular punch (diameter: 5 mm) at a pressure of 0.3 ton. The manufacturing method of the prepared fast-disintegrating tablet is shown in Table 8 below (Preparation Example 2).

Manufacturing method Preparation 2 Usage (mg/T) weight (%) excipient Flow-lac 100 87.0625 99.5 lubricant magnesium stearate 0.4375 0.5 Total mass (mg) 87.5 Compression pressure (ton) 0.3

Step 3) Assembly of parts and manufacture of oral drug delivery device

<Step 3: Placing the second agent 500, the insert 300, and the first agent 400 in the capsule body 100 and coupling the capsule cap 200>

Among the parts manufactured in Preparation Examples 1-10 to 1-12 of Step 1, the first magnetic member 230 and the second magnetic member 340 are mounted on the lower end of the capsule cap 200 and the upper end of the insert 300, respectively. then assemble In addition, the first formulation 400 prepared in Preparation Example 2 of step 2 and the commercially available 10 mg baclofen drug formulation (Prex tab®) were inserted into the capsule body 100 as the second formulation 500 . Accordingly, an oral drug delivery device for controlling the drug release rate according to an embodiment of the present invention was prepared. (Examples 10 to 12) Each configuration of each manufactured part is shown in Table 9 below.

Example 10 Example 11 Example 12 Parts of drug delivery device Preparation Example 1-10 Preparation 1-11 Preparation 1-12 Sokbung Haejeong Preparation 2 marketed drug Baclofen 10 mg (Prex tab ^® )

<Experimental Example 3: Optimization confirmation test of release rate controlled oral drug delivery device prepared according to Examples 10 to 12>

In order to confirm the drug dissolution of the release rate controlled oral drug delivery device prepared in Examples 10 to 12, a dissolution test was performed in a pH 1.2 solution according to the second method of the dissolution test method of the Korean Pharmacopoeia. The conditions of the dissolution test are as shown in Table 5 above, and the baclofen drug concentration in the eluate was analyzed by HPLC-UV. The analysis conditions for baclofen are shown in Table 6 above.

The dissolution profile obtained through the dissolution test is shown in FIG. 16, and the target value and the measured value of the time taken until 80% dissolution (T80) are shown in Table 10. As shown in FIG. 16 and Table 10, when the dissolution test was performed by inserting the 10 mg general release tablet of baclofen into the oral drug delivery device for controlling the release rate of the present invention, the time taken until the actual dissolution of 80% (T80) was It was confirmed that the average absolute error was within 0.6 hours compared to the target T80, and the release of the drug formulation could be delayed until a desired time through the release rate control oral drug delivery device of the present invention.

Example 10 Example 11 Example 12 Target value of time to 80% dissolution (T80) (h) 2 4 6 Actual observation of time to 80% dissolution (T80) (h) 1.81 ± 0.29 3.7 ± 0.65 5.59 ± 0.42 mean absolute error (h) 0.36 0.6 0.38

In the above, preferred embodiments have been shown and described, but the present invention is not limited to the specific embodiments described above, and common knowledge in the technical field to which the invention pertains without departing from the gist of the invention as claimed in the claims is not limited. Various modifications are possible by the possessor, of course, and these modifications should not be individually understood from the technical spirit or perspective of the present invention.

100: capsule body
110: main body
120: drug storage space
130: lateral opening
140: emission opening
200: capsule cap
210: cap body
220: fitting projection
230: first magnetic member
240: fixed groove
250: fixing member
260: gas filling space
300: insert
310: side wall portion
320: through hole
330: support surface portion
340: second magnetic member
350: fixed groove
400: first agent
500: second agent

Claims (11)

Capsule body having an upper open medicament storage space;
a capsule cap coupled to the capsule body and covering the medicament storage space from above;
an insert positioned in the medicament storage space and disposed under the capsule cap and vertically displaceable in the medicament storage space;
a first agent consisting of a three-dimensional material having a predetermined height, positioned in the medicament storage space, and disposed between the capsule cap and the insert to space the capsule cap and the insert; and
a second agent disposed in the drug storage space and disposed under the insert;
The capsule body
a lateral opening laterally opened to laterally open the medicament storage space, and
and a discharge opening positioned below the lateral opening and opening the medicament storage space,
The insert includes a through hole penetrating up and down,
When the first agent is positioned between the insert and the capsule cap, the lateral opening is in an open state, and the medicament storage space is opened to the outside through the lateral opening and the through hole,
When the first agent is removed and the distance between the insert and the capsule cap is reduced, the insert covers the lateral opening so that the lateral opening is in a closed state, and the second agent is released through the release opening A rate controlled oral drug delivery device. The method according to claim 1,
The discharge opening is
A controlled-release oral drug delivery device having a penetrating area smaller than the lateral opening. The method according to claim 1,
The capsule cap includes a first magnetic member,
The insert includes a second magnetic member,
The first magnetic member and the second magnetic member generate an attractive force between each other,
When the first agent is removed, the insert is displaced in the capsule cap direction by the attractive force of the first magnetic member and the second magnetic member. 4. The method of claim 3,
The insert is
It includes a side wall portion constituting the side circumferential surface of the insert,
The side wall portion,
When the insert is in a closed state, the release rate control oral drug delivery device for closing the lateral opening from the inside. 5. The method according to claim 4,
The insert is
A controlled release rate oral drug delivery device comprising a support surface for supporting the first agent under the first agent. 6. The method of claim 5,
The second magnetic member is a release rate control oral drug delivery device fixed to the support surface portion. 4. The method according to claim 3,
The first magnetic member is a release rate control oral drug delivery device fixed to the bottom surface of the capsule cap. The method according to claim 1,
The dissolution rate of the first agent is,
An oral drug delivery device with a controlled release rate faster than the dissolution rate of the second agent. The method according to claim 1,
The first agent is
A controlled-release oral drug delivery device comprising a mixture of lactose (Flow-lac 100) and magnesium stearate in a ratio of 99.5:0.5. The method according to claim 1,
The capsule cap is
An oral drug delivery device for controlling the release rate having a buoyant force by having a gas-filled space in which gas is contained therein. In the method for manufacturing the controlled release rate oral drug delivery device of any one of claims 1 to 10,
manufacturing the capsule body, capsule cap, and insert;
preparing the first formulation; and
After injecting the second agent into the capsule body, disposing the insert and the first agent and coupling the capsule cap; A method of manufacturing a controlled release rate oral drug delivery device comprising a.

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